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Thursday, August 07, 2014

Could Canadian patients be prevented from accessing experimental Ebola drugs, too? You bet they could!

Ok, so I'm a tad bit lazy. Sections of the post below are actually a few months old and I'm re-posting them here, because of the current debate about access to the experimental drug deployed in the case of the two Ebola missionaries in the United States.

First things first though, on the current debate: There has been a bit of a storm in a teacup about the question of whether or not it is just to provide an experimental treatment for Ebola to two sick missionaries who returned home to the United States from West Africa while denying it to dying Africans. Art Caplan has provided a reasonable analysis of the issues in a Washington Post OpEd. I disagree with him on the reasons for why the agent cannot be produced now in larger quantities and shipped to West Africa (poor start-up company and all that jazz). There is no reason to accept an artificial scarcity (i.e. human regulation made) as a kind of natural law, inevitable and beyond our control. Still, Caplan is right, it would be difficult to provide the medication locally in West Africa where it's needed, due to the relatively fragile nature of the experimental agent (it needs special handling, be kept in a freezer and whatnot). And yes, imagine the drug actually was a dud, potentially doing more harm then good. The same professional do-gooders shouting now racism and demanding delivery of the medication to Africa would turn around before you can say 'ouch' and excitedly shout 'exploitation' and 'African guinea pigs' and, yes, 'racism', because that charge usually sticks.

From the published reports about the experimental agent it's unclear - to me - at what stage in the R&D process it is. It seems to me - I might be mistaken here - that the drug hasn't undergone phase 1 clinical trials (i.e. how dangerous to human health is it?). From the experience with the two missionaries it seems at least as if it ain't too toxic. Still, two folks count for all scientific intent and purposes as an anecdote. Not a big surprise though, that proper trials have not been undertaken, given how quick people die, and in what locations they usually die. Doing placebo-controlled studies - no doubt the methodological gold standard under the circumstances - also seems a dicey proposition seeing the high mortality rate among infected people.

Fundamentally though, the question is whether knowledgable patients suffering from catastrophic illnesses should be permitted to access experimental drugs. Ebola is just the latest disease triggering this debate. It turns out, the situation the African patients find themselves in isn't that different to the situation faced by Canadians suffering from other catastrophic diseases. It's here where my mentioned older post kicks in...

Imagine you suffer from a catastrophic kind of illness, an illness that’s invariably going to kill you in the near future. Everything that you and your doctor know about the illness suggests that your death will be anything but peaceful. Doctors can deal with some of your symptoms and palliative care can address some of the pain you are experiencing. But that’s about it.

Sadly this scenario isn’t unrealistic. Many Canadians face this sort of situation today.

During a scheduled visit to your specialist doctor you learn that there’s a brand-new drug currently being tested that might just save your life, if it worked that is. The doctor has already inquired with the researchers testing the drug in a phase-three clinical trial and you would be eligible to participate in that trial.

Phase-three clinical trials are trials at which stage in the drug research and development process we know what its safety profile looks like and we have pretty good evidence to think that it’s effective to some extent. That is so because during earlier trials, involving initially animals and eventually other patients, sufficient evidence has been accumulated to justify letting the phase-three trial go ahead. Now the doctors are trying to recruit a fairly large number of patients in order to establish whether the drug is as good as they thought it is. The nature of your disease is such though that there is no standard therapy around to assist your struggle for survival. The trial design in such cases demands that the experimental agent is tested against a placebo control, a dummy pill. That’s done because we need to know, before doctors can confidently prescribe the drug to patients like yourself, that the drug is doing better than what is the status quo – ie no drug. It’s always possible that an experimental drug actually does worse than the dummy pill.

Now, ask yourself, if you were that patient: Would you be willing to participate in a last-chance clinical trial where you’d have a 50:50 chance of getting a dummy pill? You know already what the dummy pill would achieve: your death. Would you trust the investigators to pull the plug quickly enough for you to survive if they discovered that the experimental drug actually works? In case you want to get a better handle on how it feels to be faced with this sort of decision, check out this blog (adriennes.blog.com) by a Toronto-based melanoma patient.

Many people suffering catastrophic illnesses flat-out refuse to participate in research that’s designed as I have described it. Their argument is not about the trial methodology, it is sound. Their argument is about the ethics of providing dying people with a coercive offer: join my clinical research project on my conditions or die a predictably horrible death.

The good news is that the story doesn’t end here. It has been recognized by regulators both in Canada and elsewhere that such coercive offers to people fighting for their very survival are incompatible with the fundamental values of liberal democracies. We must not reduce patients suffering catastrophic illnesses to mere means to achieve our research objectives. While that’s nothing much other than an honorable principle, there’s also a more pragmatic reason for this. I’ll get to that in a moment.

Health Canada actually permits people who suffer catastrophic illnesses to access drugs that are in the clinical trials system, and they can do so without actually participating in the clinical trials I mentioned earlier. The agency runs a Special Access Program for these sorts of patients. The program permits patients to access the experimental agent without trial participation. In return they promise to have their doctors monitor the impact of the drug carefully and report it back to the manufacturer or whoever runs the clinical trial. One of the ethical reasons for this I have just mentioned. The pragmatic reason for this solution is this: it was discovered during the early days of the AIDS epidemic, when no life-preserving medication existed, that patients who are coerced into placebo controlled trials will simply cheat in order to get access to the actual experimental drug. HIV-infected people enrolled in ostensibly placebo-controlled trials and then took their drugs to chemists to find out who did and who didn’t get the active agent. They then started sharing the actual drug and dumped the placebo. That, of course, rendered the trial pretty useless. True volunteers would have accepted the uncertainties and volunteered to test whether the experimental agent is any better than the placebo control.

The problem patients with catastrophic disease who wish to access experimental drugs through our Special Access Program face today in Canada is two-fold: Health Canada leaves it up to pharmaceutical companies to decide whether or not they provide drugs to eligible patients. Manufacturers who have trouble recruiting sufficient numbers of patients into their trials could deny patients access to the experimental drug to encourage them to join the trial on their conditions. They might also have other reasons for refusing to provide catastrophically-ill patients with access to an experimental drug. Either way, we are back to square one: a coercive situation. This problem occurs more frequently in Canada than you might think. Here is a heart wrenching appeal (http://www.youtube.com/watch?v=olwDT7NPSsM) from one such patient, who has since died. A Toronto paper contacted me about another case recently, both cases interestingly involved pharmaceutical multinational Bristol Myers Squibb refusing to provide an experimental drug that the company is testing in a phase-three clinical trial right now. This issue should be addressed by Health Canada as a matter of urgency. The other problem is that manufacturers are permitted to charge for their experimental drug. That is unreasonable. It costs typically cents to produce such medicines – I am not talking research and development costs but actual production costs. There is no reason whatsoever why pharmaceutical companies should profit from experimental drugs. They should be compelled by Health Canada to provide such agents to clinically eligible patients, while the clinical trials are ongoing and the drug isn’t formally approved as a for-pay prescription medication. If Health Canada were to address these shortcomings of the present Special Access Program it would ensure that catastrophically ill patients are given a fairer shot at actually accessing these experimental drugs.

Udo Schuklenk holds the Ontario Research Chair in Bioethics and Public Policy at Queen’s University, he tweets @schuklenk